Comparative effects of lithium and carbamazepine have been studied using receptor-mediated phosphoinositide turnover in cultured cerebellar granule cells as a model. Lithium induced a biphasic change in carbachol-induced inositol phosphate formation in a time- and dose-dependent-manner. An inhibition was seen when increasing doses of lithium (>2mM) were incubated with cells for more than 3 days. The biphasic nature of lithium's effect was unrelated to inhibition of inositol monophosphatase activity. In addition, we found that long-term treatment of cells with carbamazepine in the therapeutic concentrations attenuated carbachol-induced phosphoinositide hydrolysis. Our results strongly suggest that there is a long-term converging effect of lithium and carbamazepine on muscarinic receptor-mediated activation of phospholipase C in neurons. Long-term lithium but not carbamazepine treatment altered the level of m3-muscarinic mRNA levels. In addition, 6-week treatment of rats with haloperidol reduced carbachol-induced inositol phosphate formation in striatum and hippocampus with a similar trend in frontal cortex. Our results underscore possible relationships between attenuation of receptor-mediated phosphoinositide turnover and the anti-manic effects of these psychotropic drugs.